在CDC23的同卵性变体导致女性不孕症,其特点是卵细胞成熟缺陷
Huizhen Fan1, Zhou Zhou1,2, Wei Zheng3
1Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
Human genetics
|September 28, 2023
概括
疾病预防控制中心23的遗传变异通过破坏卵细胞成熟导致女性不孕. 这项研究确定了CDC23变种作为不孕症的新原因和潜在的遗传标记.
科学领域:
- 生殖生物学 生殖生物学
- 遗传学 是一个遗传学.
- 细胞生物学 细胞生物学
背景情况:
- 卵细胞成熟缺陷是女性不孕症的重要原因之一.
- 确定这些缺陷的遗传基础对于诊断和治疗至关重要.
- 亚纳相促进复合体/循环体 (APC/C) 对于细胞周期的进展至关重要,特别是从元相到亚纳相的过渡.
研究的目的:
- 为了确定致病基因和变异,负责女性不育与卵细胞成熟缺陷相关的病原基因和变异.
- 为了研究CDC23的作用,一个核心的APC/C子单元,在人类卵细胞成熟.
主要方法:
- 基因测序以确定三个不育个体中的变异.
- 在体外实验中评估CDC23变体 (p.Y329C和p.R330C) 对蛋白质水平和局部化的功能影响.
- 在体内研究使用小鼠模型 (Cdc23Y329C/Y329C) 来模仿患者的表型.
- 在卵细胞中评估蛋白质表达 (CDC23,APC4,securin,cyclin B1).
- 评估AZ3146治疗的治疗潜力.
主要成果:
- 在不育个体中发现了两种同卵性误解变异在CDC23中 (c.986A>G,p.Y329C和c.988C>T,p.R330C).
- 这种p.Y329C变异降低了CDC23蛋白水平,而p.R330C变异改变了CDC23在细胞和卵细胞中的定位.
- 在Cdc23Y329C/Y329C小鼠模型中,CDC23和APC4的表达以及卵细胞中securin和cyclin B1的积累减少,反映了患者的表型.
- 在小鼠模型中,AZ3146治疗成功地挽救了观察到的卵细胞成熟缺陷.
结论:
- CDC23在人类卵细胞成熟中起着至关重要的作用.
- 已识别的CDC23变异是一种新的女性不孕症遗传原因.
- 这些发现确立了CDC23变体作为诊断女性不孕症的潜在遗传标记.
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